Mechanical loading is necessary for proper development and maintenance of the musculoskeletal system. Yet, despite the profound effects of reduced mechanical loading on muscle atrophy and skeletal fragility, there has been little investigation into the physiological effects of partial weight-bearing environments, largely due to lack of a suitable animal model. We have developed a novel model of titrated weight-bearing that offers a unique capability for exploring the chronic effects of reduced quadrupedal loading in mice. The system allows studies with controlled exposure to 10-80% weight-bearing compared to normally loaded controls in an identical environment. Our preliminary data show significant muscle and bone loss following 3 weeks exposure to partial weight-bearing at 38% of body weight, but less deterioration than previously reported for full unloading via tail suspension. Our long term goal is to take advantage of this unique model to gain insight into the mechanisms underlying the musculoskeletal response to reduced mechanical loading, thereby identifying new targets for preventing musculoskeletal deterioration in situations of reduced mechanical loading, such as bed rest, immobilization, stroke, spinal cord injury and age-related reductions in physical activity. In this developmental R21 application, we propose first to extensively characterize the mechanical stimuli associated with our model using in vivo strain gage and force plate measurements, and then to determine the timing and magnitude of the musculoskeletal response to partial weight-bearing at 20, 40, and 60% of body weight, as compared to both normal weight-bearing and full hindlimb unloading via tail suspension. Establishment of a model where quadrupedal gait is maintained, yet loads can be reduced by prescribed amounts will provide the opportunity to test long-held beliefs about the minimal loading stimulus necessary to maintain bone and muscle tissue under conditions of disuse. A major advantage to developing a partial weight-bearing murine model is that it will be ideally suited for future studies designed to delineate the genetic, cell and molecular mechanisms associated with musculoskeletal adaptation to altered loading environments. PUBLIC HEALTH RELEVANCE: Disuse and reduced activity due to bed rest, immobilization, stroke, spinal cord injury along with age-related reductions in physical activity contribute to musculoskeletal injuries, including fractures. We have developed and propose to fully characterize a novel approach to studying musculoskeletal atrophy associated with disuse in which mice are exposed chronically to controlled levels of reduced body-weight loading. Our long term goal is to identify new targets and treatments for preventing musculoskeletal deterioration in situations of reduced mechanical loading.